Equine animals, e.g., horses, are affected by various metabolic disorders, including insulin resistance and hyperinsulinaemia. Such insulin-related disorders in equine animals, for example, are only rarely associated with diabetes mellitus and hyperglycemia, as it is in humans or various other mammals. However, in equine animals, insulin also regulates vital metabolic functions; e.g., insulin drives glucose into tissues such as liver, adipose, and skeletal muscle; induces vasoconstrictive and vasodilatory pathways; and regulates protein and fat metabolism. Insulin-related disorders thus have a severe and life-threatening impact on the health of equine animals. They are correlated or may be associated with a number of further equine disorders, conditions or syndromes, including impaired glucose tolerance, dyslipidemia, dysadipokinemia, obesity and/or regional adiposity, subclinical inflammation or systemic inflammation, in particular low grade systemic inflammation, which also comprises adipose tissue, Equine Metabolic Syndrome (EMS) and/or Equine Pituitary Pars Intermedia Dysfunction (PPID), also known as equine Cushing's syndrome, which are characterized e.g. by laminitis, vascular dysfunction, hypertension, hepatic lipidosis, hyperadrenocorticism and/or atherosclerosis.
In particular, insulin resistance in equine animals may be associated with EMS and/or PPID or may cause the development or progression of PPID. EMS and/or PPID may become manifest e.g., in laminitis. This devastating worldwide cause of mortality in horses is a multifactorial condition causing structural and mechanical changes in the supporting tissues within the hoof, resulting in acute and chronic pain, lameness, and potentially euthanasia. Equine laminae are highly metabolically active, and a complex microvascular bed is present. A significant body of evidence exists also for vascular dysfunction (endothelial cell dysfunction) during equine laminitis (ref. 1: Katz & Bailey, 2012). In vitro studies in equine digital vessels have shown insulin resistance mediated endothelial and/or vascular dysfunction (ref. 2: Venugopal et al., 2011). A direct link between hyperinsulinaemia and laminitis has been documented in naturally-occurring forms of the disease (ref. 3: Treiber et al., 2006). However, the mechanism by which insulin resistance and/or hyperinsulinemia cause EMS and/or PPID, in particular vascular dysfunction and/or laminitis in horses is poorly understood.
No satisfactory treatment is currently available for metabolic disorders such as insulin resistance, hyperinsulinaemia and associated disorders in equine animals, such as EMS and/or in case they are associated with or secondary to e.g., PPID, which become manifested e.g., by laminitis, vascular dysfunction, hypertension in equine animals. For instance, the use of Metformin is controversially discussed (ref. 4: Tinworth et al., 2012). Similarly, treatment of equine PPID with pergolide seems to hardly affect insulin resistance and/or hyperinsulinemia (ref. 5: Gehlen, 2014).
In human medicine, insulin resistance, e.g., when manifested as diabetes mellitus type 2, is a well-recognized condition, and may lead in particular to hyperglycemia (pathologically increased plasma glucose levels). Several oral antihyperglycemic drugs are approved for human diabetes. These drugs act, e.g., by stimulating pancreatic insulin secretion in a glucose-independent or glucose-dependent manner (sulfonylurea/meglitinides, or DPP IV inhibitors, respectively), by enhancing tissue sensitivity to insulin (biguanides, thiazolidinediones), or by slowing postprandial intestinal glucose absorption (alpha-glucosidase inhibitors).
Other antihyperglycemic approaches have been contemplated for treating diabetes and high blood sugar, including inhibition of the renal sodium-dependent glucose cotransporter SGLT2. SGLT2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood. SGLT2 inhibition thus induces glucosuria or glycosuria and may reduce blood glucose levels.
SGLT2 inhibition has not previously been contemplated for use in equine animals, in particular in insulin-resistant equine animals. In equine animals, insulin-resistance, i.e., failure of tissues to respond appropriately to insulin, generally becomes manifested as hyperinsulinemia. When insulin-resistant target tissues, e.g., skeletal muscle, have a reduced capacity for glucose uptake, the pancreas is stimulated to release more insulin, leading to hyperinsulinaemia. However, unlike in humans, e.g., insulin resistance in equine animals, e.g., horses, is generally not associated with hyperglycemia (ref. 6: Frank et al., 2011). Insulin-resistant equine animals, e.g., horses, do not appear to have high blood glucose. For that reason, it would appear to be counter-intuitive to apply an approach that reduces blood glucose by transferring glucose out of the blood into the urine, even if this was previously known in a context of high blood glucose.